The Influence of Metabolic State on Targeted Drug Delivery, Biodistribution and Efficacy of Nanoparticles

Plasma proteins have been shown to bind intravenously injected nanoparticles with high affinity and this could have potential consequences for drug delivery applications. A subset of plasma proteins, high density lipoproteins (HDLs), has been found to form a major component of the biomolecular corona of injected nanoparticles and this could possibly lead to nanoparticle therapies being diverted to HDL receptors (SCARBI).I use polystyrene nanoparticles of different surface chemistries (PS, PS-COOH and PS-NH2) and determine the affinity of lipoproteins for these nanoparticles. My findings indicate that the strength of binding of lipoproteins to nanoparticles in vitro is high enough to effect nanoparticle biodistribution in vivo. My in vitro binding studies also reveal that even with competition from other plasma proteins, lipoproteins still bind nanoparticles with moderate strength.The ability of lipoproteins to redirect nanoparticles to their receptors upon binding was investigated by using mice models lacking SCARBI. Clodronate liposomes are utilized to eliminate the effects of macrophages so that I could eliminate background biodistribution. My study demonstrates that HDLs significantly affect nanoparticle biodistribution by comparing nanoparticle uptake and plasma lipoprotein cholesterol content in both wild-type and SCARBI-/-. Interestingly, nanoparticle uptake is increased in male SCARBI-/- mice following macrophage depletion, but the opposite is observed for females. Examination of plasma lipoprotein cholesterol content suggests that differences in lipoprotein and lipid metabolism between the genders could account for such dissimilarities.To further elucidate the effects of metabolic state on nanoparticle uptake, I intravenously injected C57BL/6, KK-A^y and ob/ob mice with nanoparticles called, filomicelles. These mice are given two types of diets: a low-fat diet (4 grams/day) and a high-fat diet ad libitum. KK-A^y and ob/ob are known to become obese upon consuming diets high in fat. Following obesity status, I observed that localization of filomicelles was reduced in the liver and spleen. In another study combining obesity and B-cell lymphoma in a mouse model, I address the potential for obese individuals to have a higher risk for advancing B-cell lymphoma. My results from hematology, and histopathological examinations of spleen and lymph node tissues indicates that obesity may have the potential to advance the disease.